PROJECT SUMMARY/ ABSTRACT The current understanding of how primary tumor cells acquire the capacity to metastasize is still very limited. This becomes a major problem to find effective cures for all types of cancer, as metastatic disease accounts for the majority of cancer-related mortality. Therefore, a deep understanding of the changes that occur in primary tumor cells that lead them to acquire the ability to escape the immune system, migrate, invade, colonize and survive at distant niches is necessary. Metabolic reprogramming is at the intersection of signaling pathways and their ability to elicit cellular changes to promote increased cell survival, growth and proliferation. However, which metabolic adaptations are necessary to enable cancer cells to create a permissive microenvironment and survive the arduous process that leads to metastases remains poorly understood. Here, I propose that increased propionate metabolism is an essential metabolic adaptation that drives tumor progression and ultimately leads to metastasis. My preliminary data show that not only is increased propionate metabolism crucial for the acquisition of metastatic properties, but also that metastatic breast cancer cells are ?addicted? to this pathway. Therefore, my goal is to understand how pathways that drive metastasis regulate propionate metabolism and what functions increased propionate metabolism has during tumor progression. During the K99 phase of this award, I will determine the molecular mechanisms that regulate propionate metabolism and will evaluate if propionate metabolism affects metastasis formation in vivo. During the R00 phase of this award, I will focus on understanding what key functional roles propionate metabolism serves to support tumor progression and the development of metastases. This work will establish a new branch of metabolic signaling and expand our understanding of metabolic dependencies and their role during tumor progression. In addition to the scientific goals of this proposal, I have also proposed a comprehensive training plan during the K99 phase of the award that will prepare me for the transition to independence. This includes guidance from three renowned mentors, Drs. John Blenis, Lewis Cantley and Douglas Fearon, acquisition of new skills in immunology and the study of tumor microenvironment, training on state-of-the-art technology for isotope tracing, and development of professional skills to guide my transition to independence.